Immunotherapy of ovarian cancer with a monoclonal antibody specific for the extracellular domain of anti-Müllerian hormone receptor II.

Suparna Mazumder,Vincent K Tuohy,Valerie Swank,Anton A Komar,Justin M Johnson

doi:10.18632/oncotarget.27585

Abstract

Epithelial ovarian carcinoma (EOC) is the most prevalent and lethal form of ovarian cancer. The low five-year overall survival after EOC diagnosis indicates an urgent need for more effective ways to control this disease. Anti-Müllerian hormone receptor 2 (AMHR2) is an ovarian protein overexpressed in the majority of human EOCs. We have previously found that vaccination against the ovarian-specific extracellular domain of AMHR2 (AMHR2-ED) significantly inhibits growth of murine EOCs through an IgG-mediated mechanism that agonizes receptor signaling of a Bax/caspase-3 dependent proapoptotic cascade. To determine if a single monoclonal antibody (mAb) could inhibit growth of human EOC, we generated a panel of mAbs specific for recombinant human AMHR2-ED and characterized a candidate mAb for humanization and use in clinical trials. We found that our candidate 4D12G1 mAb is an IgG1 that shows high affinity antigen-specific binding to the 7-mer 20KTLGELL26 sequence of AMHR2-ED that facilitates induction of programmed cell death in EOC cells. Most importantly, the 4D12G1 mAb significantly inhibits growth of primary human EOCs in patient-derived xenografts (PDXs) by inducing direct apoptosis of EOC tumors. Our results support the view that a humanized 4D12G1 mAb may be a much needed and effective reagent for passive immunotherapy of human EOC.

Highlights

Epithelial ovarian carcinoma (EOC) is the most lethal of all gynecologic malignancies with postmenopausal women accounting for more than 75% of all cases [1, 2]
Since we found that safe and effective immunity against ovarian tumors can be generated by AMHR2ED-specific IgG, we generated a panel of monoclonal antibodies specific for recombinant human Anti-Müllerian hormone receptor 2 (AMHR2)-ED and characterized their binding and functional features to select a candidate monoclonal antibody (mAb) for use in human clinical trials focused on treatment of women with EOC
Our results indicate that signaling induced by binding of the 4D12G1 mAb to AMHR2 results in apoptosis of EOC cells accompanied by endocytic internalization of the mAb-AMHR2 complexes and caspase-3 mediated cleavage of poly (adenosine diphosphateribose) polymerase (PARP)-1

Summary

Introduction

Epithelial ovarian carcinoma (EOC) is the most lethal of all gynecologic malignancies with postmenopausal women accounting for more than 75% of all cases [1, 2]. There remains a great need www.oncotarget.com for more effective ways to control this disease To this end, we and others have shown that anti-Müllerian hormone receptor type II (AMHR2) is expressed in 90% of primary EOCs, 78% of borderline malignancies, 77–86% of nonEOC ovarian tumors, and 56% of malignant ascites from grades III-IV ovarian cancers [8,9,10,11]. We and others have shown that anti-Müllerian hormone receptor type II (AMHR2) is expressed in 90% of primary EOCs, 78% of borderline malignancies, 77–86% of nonEOC ovarian tumors, and 56% of malignant ascites from grades III-IV ovarian cancers [8,9,10,11] As such AMHR2 may serve as an effective target for immune control of primary and more advanced forms of EOC

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Conclusion